The 1.alpha.-hydroxylated metabolites of vitamin D--most importantly 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxyvitamin D.sub.2 --are known as highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has also been established. V. Ostrem et al, Proc. Natl. Acad. Sci. U.S.A., (1987), 84, 2610. As a consequence, many structural analogues of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogues are 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2, various side chain fluorinated derivatives of 1.alpha.,25-dihydroxyvitamin D.sub.3, and side chain homologated analogues. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds with advantageous therapeutic activity profiles and thus numerous of these compounds are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Recently, a new class of vitamin D analogues has been discovered, i.e. the so-called 19-nor-vitamin D compounds. 19-nor-vitamin D compounds are vitamin D analogues in which the ring A exocyclic methylene group (carbon 19) typical of all vitamin D compounds has been removed and replaced by two hydrogen atoms. Specifically, these compounds exhibit a selective activity profile with high potency in inducing cellular differentiation, and minimal bone calcification activity. Such a differential activity profile renders these compounds useful for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of these 19-nor-vitamin D analogues have been described (Perlman et al, Tetrahedron Letters 31, 1823 (1990); Perlman et al, Tetrahedron Letters 32, 7663 (1991), and DeLuca et al, U.S. Pat. No. 5,086,191).
In Teutsch et al, U.S. Pat. No. 4,386,085, a 19-nor-steriod (referred to as RU 486) having strong antiprogesterone and antiglucocorticosteriod activities is described. When used in conjunction with synthetic prostaglandins RU 486 terminates pregnancy, which accounts for its wide interest. In addition it has potential as an antiglucocorticoid, and antiestrogen agent.
Many analogues of RU 486 have been prepared, Etienne-Emile Baulieu: Science (1989) 245, 1351-1357, Chem. Eng. News (1991) 69 7-14, Schering's ZK 98299 (Federation Meeting 1992) 2037, all of which share with RU 486 the intact steroid A ring of progesterone with the conjugated 3-oxo-4-ene moiety. This feature is assumed to be responsible for binding to the progesterone receptor (PR).
In U.S. Pat. No. 5,397,776 vitamin D analogues with a progesterone side chain, but with the 3.beta.-hydroxycyclohexane A-ring and double bond system characteristic of vitamin D were synthesized. The compounds prepared were 20-oxo-pregnacalciferol, 1.alpha.-hydroxy-20-oxopregnacaliciferol and 19-nor-1.alpha.-hydroxy-20-oxopregnacalciferol. All three compounds were examined for binding to the PR. Of the three 20-oxo analogues, only 20-oxo-pregnacalciferol did bind to the PR, indicating that the 1.alpha.-hydroxy group in the other two vitamin D-progesterone analogues prevents binding to the PR, and the absence of the 10-19 double bond in the 19-nor compound did not make a difference. None of the above three compounds had any calcemic activity nor did they bind to the vitamin D receptor.
It has been suggested, Teutsch et al, U.S. Pat. No. 4,386,085 May 31, 1983, Etienne-Emile Baulieu: Science (1989) 245, 1351-1357, that the A ring of RU 486 is necessary for binding to the PR. The ability of 20-oxo-pregnacalciferol to bind to the PR suggests that the progesterone A ring may not play as significant a role as had been assumed. Thus, as disclosed in U.S. Pat. No. 5,397,776, 20-oxo-pregnacalciferol is useful as an antagonist of progesterone, and thus blocks progesterone from binding to the PR. Since progesterone binding is necessary to maintain pregnancy, an abortion results. Compounds that block progesterone from binding to the PR, thus have potential for use in birth control either to prevent pregnancy or to abort pregnancy.
In an ongoing effort to examine the structural features responsible for binding properties to the PR, 20-oxo-pregnacalciferol analogs with 19-nor-3-desoxy-A rings were synthesized in which the exocyclic methylene group (carbon 19) and the 3-hydroxy group of the vitamin D molecule have been replaced by hydrogen atoms. The compounds prepared were 3-desoxy-20-oxo-19-nor-pregnacalciferol and 3-desoxy-2,20-dioxo-19-nor-pregnacalciferol and their binding to the PR was examined. The 3-desoxy-20-oxo-19-nor-pregnacalciferol did bind to the PR, but to a significantly lesser degree (40%) than the previously synthesized 20-oxo-pregnacalciferol. Interestingly, the intermediate 22-alcohol and the 22-aldehyde did also bind to the PR, the latter compound binding 1.5 times more than the 20-ketone. The biological results indicate, that an oxygen function in the A ring could be essential for improved binding to the PR. Attention was then turned to the 19-nor-pregnacalciferol analog with an oxo group in the A ring. It was found that 3-desoxy-2,20-dioxo-19-nor-pregnacalciferol has almost the same binding activity to the PR as the previously examined 20-oxo-pregnacalciferol, whereas the intermediate 22-alcohol, and the 22-aldehyde and the mono-protected 2,20-dione did also bind to the PR but to a lesser degree.